The role of calcium channels in osteoporosis and their therapeutic potential.

Osteoporosis, a systemic skeletal disorder marked by diminished bone mass and compromised bone microarchitecture, is becoming increasingly prevalent due to an aging population. The underlying pathophysiology of osteoporosis is attributed to an imbalance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Osteoclasts play a crucial role in the development of osteoporosis through various molecular pathways, including the RANK/RANKL/OPG signaling axis, cytokines, and integrins. Notably, the calcium signaling pathway is pivotal in regulating osteoclast activation and function, influencing bone resorption activity. Disruption in calcium signaling can lead to increased osteoclast-mediated bone resorption, contributing to the progression of osteoporosis. Emerging research indicates that calcium-permeable channels on the cellular membrane play a critical role in bone metabolism by modulating these intracellular calcium pathways. Here, we provide an overview of current literature on the regulation of plasma membrane calcium channels in relation to bone metabolism with particular emphasis on their dysregulation during the progression of osteoporosis. Targeting these calcium channels may represent a potential therapeutic strategy for treating osteoporosis.

Association of obesity with osteoporotic fracture risk in individuals with bone metabolism-related conditions: a cross sectional analysis.

Introduction: This study aimed to investigate the individual and composite associations of different indices of obesity on osteoporotic fractures at three different sites among individuals affected by conditions influencing bone metabolism. Methods: Participants were included from the National Health and Nutrition Examination Survey (NHANES), a national cross-sectional survey. BMI and WC were used separately and in combination to evaluate the presence of obesity. Obesity was defined as BMI ≥ 30 kg/m2, WC ≥ 88 cm in females, and WC ≥ 102 cm in males. Associations between obesity and osteoporotic fractures were assessed using multivariable logistic regression and OR curves. Associations modified by age, sex, race, and alcohol consumption were also evaluated. Results: A total of 5377 participants were included in this study. In multivariable logistic regression analyses, we found that BMI, WC, BMI defining obesity, and WC defining obesity were negatively associated with hip fracture (all p < 0.05). However, harmful associations between WC and BMI defining obesity and spine fracture were found (all p < 0.05). OR curves revealed that BMI and WC had a linear relationship with hip and spine fractures (all P for non-linearity >0.05). Further analyses showed that the highest WC quartile was harmfully associated with a higher risk of spine fractures (p < 0.05). Obese participants diagnosed by both BMI and WC were less likely to have hip fractures but more likely to have spine fractures (all P for trend <0.05). A significant interaction between age (Ref: age < 50 years) and BMI and WC was detected for hip fractures (all P for interaction <0.05). Discussion: In people with conditions influencing bone metabolism, obesity diagnosed by BMI and WC was associated with a lower risk of hip fracture, while obesity diagnosed by BMI and the highest WC quartile were associated with a higher risk of spine fracture.

Analysis of risk factors and predictive efficacy of senile osteoporosis fracture based on biochemical indicators of bone metabolism.

A total of 254 elderly OS patients diagnosed and treated in our hospital during May 2019 to April 2022 was randomly picked, of which 100 patients were finally enrolled. Patients were divided into OS fracture group and non-fracture group according to whether they had OS fracture. The contents of bone mineral density (BMD) and bone metabolism biochemical indexes, including Dickkopf1 (DKK-1), sclerostin (SOST), osteoprotegerin (OPG), osteopontin (OPN), osteocalcin (BGP) and 25 hydroxyvitamin D (25 (OH) D) were detected in lumbar L2c4 and left femoral greater trochanter. The correlation between bone metabolism and BMD was evaluated using Pearson analysis. The risk factors of OS fracture were analyzed using Multivariate logistic regression analysis. The predictive value of biochemical indexes of bone metabolism on the risk of OS fracture was analyzed using ROC curve.

In vitro osteoclast differentiation enhanced by hepatocyte supernatants from high-fat diet mice.

Non-alcoholic fatty liver disease (NAFLD) is associated with abnormal bone metabolism, potentially mediated by elevated levels of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-ɑ) and interleukin 6 (IL-6). This study aims to investigate the direct regulatory effects of liver tissues on osteoblast and osteoclast functions in vitro, focusing on the liver-bone axis in NAFLD. Twelve-week-old C57BL/6 mice were fed either a control diet or a high-fat diet (HFD) for 12 weeks. Bone structural parameters were assessed using microCT. Primary hepatocyte cultures were established from control and HFD-fed C57BL/6 mice, as well as IL-6-/- and TNF-α-/- mice. The supernatants from these hepatocyte cultures were used to induce differentiation in bone marrow cell-derived osteoblasts and osteoclasts in vitro. Results showed that mice on a HFD exhibited increased lipid infiltration in liver and bone marrow tissues, alongside reduced bone mass. Moreover, the supernatants from hepatocyte cultures from mice on a HFD displayed elevated TNF-α and IL-6 levels. These supernatants, particularly those derived from HFD-fed and IL-6-/- mice, significantly enhanced osteoclast differentiation in vitro. In contrast, supernatants from TNF-α-/- mice did not significantly affect osteoblast or osteoclast differentiation in vitro. In conclusions, this current study suggested that fatty liver tissues may negatively impact bone metabolism. Additionally, knockout of TNF-α and IL-6 genes revealed distinct influence on osteoblast and osteoclast functions, highlighting the complex interplay between live pathology and bone health.

Amyloid-ß peptide treatment reverses bone loss in the mandibular condyle via Wnt signalling pathway.

Objective: To explore the effect of amyloid-ß peptide (Aß) on mandibular condyle to develop a new treatment for postmenopausal women with Temporomandibular joint osteoarthritis. Methods: A murine bone loss model was established by ovariectomy. Microstructure parameters of the condyle were measured by microcomputed tomography before and after intraperitoneal injection with Aß. Flow cytometry, Alizarin red staining, RT-qPCR assays, FITC/PI staining, Oil Red O staining and western blotting were used to evaluate the effect of Aß on the osteogenic differentiation of mouse bone marrow stromal stem cells (mBMSCs). Results: In vivo, condylar microstructure parameters increased. Serum osteoprotegerin and procollagen type 1 N propeptide increased in a dose-dependent manner after the injection of Aß, which were opposite the changes observed in c-terminal telopeptides of type I collagen, tumor necrosis factor-α and the high serum level of leptin. In vitro, Aß promoted calcium nodule formation in the cells. The expression of ALP, Runx2, osteorix and osteocalcin increased significantly. The expression of mRNAs related to the Wnt signaling pathway was significantly upregulated, which could be blocked by DKK1. Conclusion: Aß can reverse bone loss in the mandibular condyle in ovariectomized mice through promoting the osteogenic differentiation of mBMSCs via the Wnt pathway.

Long non-coding and circular RNAs in osteoporosis: Translation to clinical practice.

Non-coding RNAs (ncRNAs) belong to a class of untranslated nucleic acids involved in regulation of gene expression. ncRNAs are categorized as small (<200 ribonucleotides in length), i.e., microRNAs (miRNAs), and long ncRNAs (lncRNAs) (200 to thousands of ribonucleotides in length) and circular RNAs (circRNAs). In contrast to miRNAs, the roles of lncRNAs in general and circRNAs in bone metabolism specifically are not well understood. As such, a comprehensive understanding of these RNA species in bone turnover could be of great value in the development of new diagnostic tools and therapeutic targets. Unfortunately, measurement of these unique RNAs lacks standardization, a component critical to clinical translation. This review examines the potential role of lncRNA and circRNA as bone biomarkers, the need for validated and standardized measurement and challenges thereof.

Effects of tibolone combined with zoledronic acid on bone density, bone metabolism, and pain in postmenopausal patients with osteoporosis.

OBJECTIVE: To explore the efficacy and safety of tibolone combined with zoledronic acid in the treatment of postmenopausal osteoporosis (PMO). METHODS: We conducted a retrospective analysis of 121 PMO patients from March 2019 to July 2021. Patients were divided into two groups based on treatment regimen: an observation group (n=62) receiving zoledronic acid combined with tibolone and a control group (n=59) receiving tibolone monotherapy. We evaluated and compared therapeutic efficacy, bone mineral density, bone metabolism markers (osteocalcin, serum C-terminal telopeptide of type I collagen, and bone alkaline phosphatase), pain, knee joint function, incidence of fragility fractures, and adverse reactions. Logistic regression analysis was used to evaluate risk factors affecting treatment efficacy. RESULTS: The observation group showed a significantly higher therapeutic effect (96.77%) compared to the control group (83.05%), and a lower incidence of fragility fractures (P=0.012). Before treatment, there were no significant differences in bone mineral density, bone metabolism markers, pain status, or knee function between the two groups (all P>0.05). However, after treatment, evaluations showed marked improvements in these parameters in both groups, with more significant enhancements observed in the observation group (all P<0.001). The incidence of adverse reactions did not significantly differ between the groups (20.97% vs 13.56%, P=0.282). Logistic regression analysis identified the use of tibolone combined with zoledronic acid as a protective factor for effective treatment. CONCLUSIONS: Tibolone combined with zoledronic acid significantly increases bone mineral density, improves bone metabolism, and reduces pain in PMO patients, with a safety profile comparable to that of monotherapy. This regimen should be considered for clinical use in treating PMO.

Tibial Damage Caused by T-2 Toxin in Goslings: Bone Dysplasia, Poor Bone Quality, Hindered Chondrocyte Differentiation, and Imbalanced Bone Metabolism.

T-2 toxin, the most toxic type A trichothecene, is widely present in grain and animal feed, causing growth retardation and tissue damage in poultry. Geese are more sensitive to T-2 toxin than chickens and ducks. Although T-2 toxin has been reported to cause tibial growth plate (TGP) chondrodysplasia in chickens, tibial damage caused by T-2 toxin in geese has not been fully demonstrated. This study aims to investigate the adverse effects of T-2 toxin on tibial bone development, bone quality, chondrocyte differentiation, and bone metabolism. Here, forty-eight one-day-old male Yangzhou goslings were randomly divided into four groups and daily gavaged with T-2 toxin at concentrations of 0, 0.5, 1.0, and 2.0 mg/kg body weight for 21 days, respectively. The development of gosling body weight and size was determined by weighing and taking body measurements after exposure to different concentrations of T-2 toxin. Changes in tibial development and bone characteristics were determined by radiographic examination, phenotypic measurements, and bone quality and composition analyses. Chondrocyte differentiation in TGP and bone metabolism was characterized by cell morphology, tissue gene-specific expression, and serum marker levels. Results showed that T-2 toxin treatment resulted in a lower weight, volume, length, middle width, and middle circumference of the tibia in a dose-dependent manner (p < 0.05). Moreover, decreased bone-breaking strength, bone mineral density, and contents of ash, Ca, and P in the tibia were observed in T-2 toxin-challenged goslings (p < 0.05). In addition, T-2 toxin not only reduced TGP height (p < 0.05) but also induced TGP chondrocytes to be disorganized with reduced numbers and indistinct borders. As expected, the apoptosis-related genes (CASP9 and CASP3) were significantly up-regulated in chondrocytes challenged by T-2 toxin with a dose dependence, while cell differentiation and maturation-related genes (BMP6, BMP7, SOX9, and RUNX2) were down-regulated (p < 0.05). Considering bone metabolism, T-2 toxin dose-dependently and significantly induced a decreased number of osteoblasts and an increased number of osteoclasts in the tibia, with inhibited patterns of osteogenesis-related genes and enzymes and increased patterns of osteoclast-related genes and enzymes (p < 0.05). Similarly, the serum Ca and P concentrations and parathyroid hormone, calcitonin, and 1, 25-dihydroxycholecalciferol levels decreased under T-2 toxin exposure (p < 0.05). In summary, 2.0 mg/kg T-2 toxin significantly inhibited tibia weight, length, width, and circumference, as well as decreased bone-breaking strength, density, and composition (ash, calcium, and phosphorus) in 21-day-old goslings compared to the control and lower dose groups. Chondrocyte differentiation in TGP was delayed by 2.0 mg/kg T-2 toxin owing to cell apoptosis. In addition, 2.0 mg/kg T-2 toxin promoted bone resorption and inhibited osteogenesis in cellular morphology, gene expression, and hormonal modulation patterns. Thus, T-2 toxin significantly inhibited tibial growth and development with a dose dependence, accompanied by decreased bone geometry parameters and properties, hindered chondrocyte differentiation, and imbalanced bone metabolism.

Effect of type 2 diabetes on biochemical markers of bone metabolism: a meta-analysis.

Objective: This meta-analysis aims to examine differences in biochemical markers of bone metabolism between individuals with type 2 diabetes (T2DM) and non-T2DM control groups. Materials and methods: Two independent evaluators searched five databases: PubMed, EMBASE, EBSCOhost, Web of Science, and the Cochrane Library. We aimed to identify observational studies investigating the impact of T2DM on biochemical markers of bone metabolism. Literature retrieval covered the period from the establishment of the databases up to November 2022. Studies were included if they assessed differences in biochemical markers of bone metabolism between T2DM patients and non-T2DM control groups using cross-sectional, cohort, or case-control study designs. Results: Fourteen studies were included in the analysis, comprising 12 cross-sectional studies and 2 cohort studies. Compared to the non-T2DM control group, T2DM patients showed reduced levels of Osteocalcin and P1NP, which are markers of bone formation. Conversely, levels of Alkaline phosphatase and Bone-specific alkaline phosphatase, other bone formation markers, increased. The bone resorption marker CTX showed decreased levels, while TRACP showed no significant difference. Conclusion: In individuals with T2DM, most bone turnover markers indicated a reduced rate of bone turnover. This reduction can lead to increased bone fragility despite higher bone mineral density, potentially increasing the risk of osteoporosis.Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php? identifier CRD42022366430.

Effectiveness of desertliving cistanche in managing hyperlipidemic osteoporosis in ovariectomized rats through the PI3K/AKT signaling pathway.

BACKGROUND: To aim of this study is to assess the mechanism through which Desertliving Cistanche modulates the PI3K/AKT signaling pathway in the treatment of hyperlipidemic osteoporosis in ovariectomized rats. METHODS: We randomly assigned specific-pathogen-free (SPF) rats into five groups (n = 10 per group). The normal control group received a standard diet, while the model group, atorvastatin group, diethylstilbestrol group, and treatment group were fed a high-fat diet. Four weeks later, bilateral ovariectomies were conducted, followed by drug interventions. After six weeks of treatment, relevant indicators were compared and analyzed. RESULTS: Compared to the normal control group, rats in the model group exhibited blurred trabecular morphology, disorganized osteocytes, significantly elevated levels of bone-specific alkaline phosphatase (BALP), bone Gla-protein (BGP), total cholesterol (TC), tumor necrosis factor-α (TNF-α), and receptor activator of NF-κB ligand (RANKL). Also, the model group revealed significantly reduced levels of ultimate load, fracture load, estradiol (E2), bone mineral density (BMD), osteoprotegerin (OPG), and phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt) in femoral tissue. The atorvastatin group presented with higher TC and TNF-α levels compared to the normal control group. Conversely, the treatment group demonstrated enhanced trabecular morphology, denser structure, smaller bone marrow cavities, and reduced BALP, BGP, TC, TNF-α, and RANKL levels. Furthermore, the treatment group exhibited higher levels of E2, BMD, OPG, and PI3K and Akt in bone tissue compared to the model group. The treatment group also had lower TC and TNF-α levels than the atorvastatin group. Biomechanical analysis indicated that after administration of Desertliving Cistanche, the treatment group had reduced body mass, increased ultimate and fracture load of the femur, denser bone structure, smaller bone marrow cavities, and altered periosteal arrangement compared to the model group. CONCLUSION: Our study revealed that Desertliving Cistanche demonstrated significant efficacy in preventing and treating postmenopausal hyperlipidemic osteoporosis in rats.

The mechanism of bone metabolism in a Sprague Dawley rat model of mandibular osteoradionecrosis.

Background: Osteoradionecrosis (ORN) is a serious complication of radiotherapy for head and neck cancer. There is currently a lack of data on the dynamic expression of genes related to bone remodeling during the development of mandibular ORN. This study aimed to establish an animal model of ORN in Sprague Dawley (SD) rats, detect the expression of genes related to bone metabolism, observe morphological changes, and clarify the mechanism of ORN. Methods: A total of 24 male SD rats in group 1 were randomly divided into four groups (n=6/group): group a, normal control; group b, simple tooth extraction; group c, simple radiation; and group d, radiation extraction group. The right mandible of rats in groups c and d was irradiated with a single dose of 35 Gy. The right mandibles were taken from each group for morphological observation 90 days after irradiation. SD rats in group 2 (n=144) were randomly divided into four groups (in similar fashion to group 1 but with groups a', b', c', and d'). Samples were collected at six time points after irradiation. Histopathological changes were observed, and Western blotting (WB) was used to analyze protein expression. Results: The formation of dead bone and pathological fracture was visible under micro-computed tomography (micro-CT), and tissue biopsy showed late fibrosis repair. In group d', osteogenesis and osteoclasis coexisted in the early irradiation stage. Vascular endothelial growth factor (VEGF) receptor expression was lower in groups c' and d' than in group a'. On day 45, runt-related transcription factor 2 (RUNX2) expression in group d' was lower than that in the other groups. The ratio of receptor activator of nuclear factor-κß ligand to osteoprotegerin (RANKL:OPG) differed significantly among groups b', c', and d' on the 45th day (d' > c' > b'). Conclusions: Radiation and vascular function damage resulted in the lower expression of VEGF. The first 15 days after radiation was mainly characterized by new bone formation. After 15 days, bone resorption increased. Tooth extraction trauma can aggravate the bone metabolism imbalance and promote ORN occurrence. These findings shed light on the mechanism of ORN.

The emerging role of tranexamic acid and its principal target, plasminogen, in skeletal health.

The worldwide burden of skeletal diseases such as osteoporosis, degenerative joint disease and impaired fracture healing is steadily increasing. Tranexamic acid (TXA), a plasminogen inhibitor and anti-fibrinolytic agent, is used to reduce bleeding with high effectiveness and safety in major surgical procedures. With its widespread clinical application, the effects of TXA beyond anti-fibrinolysis have been noticed and prompted renewed interest in its use. Some clinical trials have characterized the effects of TXA on reducing postoperative infection rates and regulating immune responses in patients undergoing surgery. Also, several animal studies suggest potential therapeutic effects of TXA on skeletal diseases such as osteoporosis and fracture healing. Although a direct effect of TXA on the differentiation and function of bone cells in vitro was shown, few mechanisms of action have been reported. Here, we summarize recent findings of the effects of TXA on skeletal diseases and discuss the underlying plasminogen-dependent and -independent mechanisms related to bone metabolism and the immune response. We furthermore discuss potential novel indications for TXA application as a treatment strategy for skeletal diseases.

Bone Marrow Adipose Tissue as a Critical Regulator of Postmenopausal Osteoporosis - A Concise Review.

Postmenopausal osteoporosis (PMOP) is a major health problem affecting millions of women worldwide. PMOP patients are often accompanied by abnormal accumulation of bone marrow adipose tissue (BMAT). BMAT is a critical regulator of bone homeostasis, and an increasing BMAT volume is negatively associated with bone mass reduction or fracture. BMAT regulates bone metabolism via adipokines, cytokines and the immune system, but the specific mechanisms are largely unknown. This review emphasizes the impact of estrogen deficiency on bone homeostasis and BMAT expansion, and the mechanism by which BMAT regulates PMOP, providing a promising strategy for targeting BMAT in preventing and treating PMOP.

Metabolic Bone Disease.

Metabolic bone diseases encompass a group of disorders characterized by abnormalities in bone metabolism, structure, or mineralization. These disorders negatively impact overall health and quality of life and place individuals at high risk for fracture, which may increase morbidity and mortality. Clinicians should understand who is at risk for these disorders, select individuals who warrant further workup, determine appropriate laboratory and imaging evaluation, interpret results in a clinical context, and choose an optimal management strategy based on the individual patient.

An atlas of brain-bone sympathetic neural circuits in mice.

There is clear evidence that the sympathetic nervous system (SNS) mediates bone metabolism. Histological studies show abundant SNS innervation of the periosteum and bone marrow-these nerves consist of noradrenergic fibers that immunostain for tyrosine hydroxylase, dopamine beta-hydroxylase, or neuropeptide Y. Nonetheless, the brain sites that send efferent SNS outflow to the bone have not yet been characterized. Using pseudorabies (PRV) viral transneuronal tracing, we report, for the first time, the identification of central SNS outflow sites that innervate bone. We find that the central SNS outflow to bone originates from 87 brain nuclei, sub-nuclei, and regions of six brain divisions, namely the midbrain and pons, hypothalamus, hindbrain medulla, forebrain, cerebral cortex, and thalamus. We also find that certain sites, such as the raphe magnus (RMg) of the medulla and periaqueductal gray (PAG) of the midbrain, display greater degrees of PRV152 infection, suggesting that there is considerable site-specific variation in the levels of central SNS outflow to the bone. This comprehensive compendium illustrating the central coding and control of SNS efferent signals to bone should allow for a greater understanding of the neural regulation of bone metabolism, and importantly and of clinical relevance, mechanisms for central bone pain.

Measurement of energy availability in highly trained male endurance athletes and examination of its associations with bone health and endocrine function.

PURPOSE: Despite the introduction of Relative Energy Deficiency in Sport (RED-s) in 2014, there is evidence to suggest that male endurance athletes still present with a high prevalence of low energy availability (LEA). Previous findings suggest that energy availability (EA) status is strongly correlated with impairments in endocrine function such as reduced leptin, triiodothyronine (T3), and insulin, and elevated bone loss. This study aimed to report the current EA status, endocrine function and bone health of highly trained Irish male endurance athletes. METHODS: In this cross-sectional study, participants (n = 3 triathletes; n = 10 runners) completed a 7-day testing period during the competition season using lab-based measures, to ascertain EA status, hormone level and rates of bone metabolism. Serum blood samples were obtained to assess hormone levels and markers of bone metabolism. RESULTS: Mean EA was < 30 kcal/kg lean body mass (LBM)/day in 76.9% of athletes. There was a strong association between LEA and low carbohydrate intake, and lower LBM. Mean levels of insulin, IGF-1 and leptin were significantly lower than their reference ranges. Elevated mean concentrations of ß-CTX and a mean P1NP: ß-CTX ratio < 100, indicated a state of bone resorption. CONCLUSION: The EA level, carbohydrate intake, hormone status and bone metabolism status of highly trained male endurance athletes are a concern. Based on the findings of this study, more frequent assessment of EA across a season is recommended to monitor the status of male endurance athletes, in conjunction with nutritional education specific to EA and the associated risks.

Exploration of bone metabolism status in the distal femur of mice at different growth stages.

The mouse femur, particularly the distal femur, is commonly utilized in orthopedic research. Despite its significance, little is known about the key events involved in the postnatal development of the distal femur. Therefore, investigating the development process of the mouse distal femur is of great importance. In this study, distal femurs of CD-1 mice aged 1, 2, 4, 6, and 8 weeks were examined. We found that the width and height of the distal femur continued to increase till the 4th week, followed with stabilization. Notably, the width to height ratio remained relatively consistent with age. Micro computed tomography analysis demonstrated gradual increases in bone volume/tissue volume, trabecular number, and trabecular thickness from 1 to 6 weeks, alongside a gradual decrease in trabecular separation. Histological analysis further indicated the appearance of the secondary ossification center at approximately 2 weeks, with ossification mostly completed by 4 weeks, leading to the formation of a prototype epiphyseal plate. Subsequently, the epiphyseal plate gradually narrowed at 6 and 8 weeks. Moreover, the thickness and maturity of the bone cortex surrounding the epiphyseal plate increased over time, reaching peak cortical bone density at 8 weeks. In conclusion, to enhance model stability and operational ease, we recommend constructing conventional mouse models of the distal femur between 4 and 8 weeks old.

Microbiota and Resveratrol: How Are They Linked to Osteoporosis?

Osteoporosis (OP), which is characterized by a decrease in bone density and increased susceptibility to fractures, is closely linked to the gut microbiota (GM). It is increasingly realized that the GM plays a key role in the maintenance of the functioning of multiple organs, including bone, by producing bioactive metabolites such as short-chain fatty acids (SCFA). Consequently, imbalances in the GM, referred to as dysbiosis, have been identified with a significant reduction in beneficial metabolites, such as decreased SCFA associated with increased chronic inflammatory processes, including the activation of NF-κB at the epigenetic level, which is recognized as the main cause of many chronic diseases, including OP. Furthermore, regular or long-term medications such as antibiotics and many non-antibiotics such as proton pump inhibitors, chemotherapy, and NSAIDs, have been found to contribute to the development of dysbiosis, highlighting an urgent need for new treatment approaches. A promising preventive and adjuvant approach is to combat dysbiosis with natural polyphenols such as resveratrol, which have prebiotic functions and ensure an optimal microenvironment for beneficial GM. Resveratrol offers a range of benefits, including anti-inflammatory, anti-oxidant, analgesic, and prebiotic effects. In particular, the GM has been shown to convert resveratrol, into highly metabolically active molecules with even more potent beneficial properties, supporting a synergistic polyphenol-GM axis. This review addresses the question of how the GM can enhance the effects of resveratrol and how resveratrol, as an epigenetic modulator, can promote the growth and diversity of beneficial GM, thus providing important insights for the prevention and co-treatment of OP.

Comparative Analysis of Myokines and Bone Metabolism Markers in Prepubertal Vegetarian and Omnivorous Children.

The role of bone and muscle as endocrine organs may be important contributing factors for children's growth and development. Myokines, secreted by muscle cells, play a role in regulating bone metabolism, either directly or indirectly. Conversely, markers of bone metabolism, reflecting the balance between bone formation and bone resorption, can also influence myokine secretion. This study investigated a panel of serum myokines and their relationships with bone metabolism markers in children following vegetarian and omnivorous diets. A cohort of sixty-eight healthy prepubertal children, comprising 44 vegetarians and 24 omnivores, participated in this study. Anthropometric measurements, dietary assessments, and biochemical analyses were conducted. To evaluate the serum concentrations of bone markers and myokines, an enzyme-linked immunosorbent assay (ELISA) was used. The studied children did not differ regarding their serum myokine levels, except for a higher concentration of decorin in the vegetarian group (p = 0.020). The vegetarians demonstrated distinct pattern of bone metabolism markers compared to the omnivores, with lower levels of N-terminal propeptide of type I procollagen (P1NP) (p = 0.001) and elevated levels of C-terminal telopeptide of type I collagen (CTX-I) (p = 0.018). Consequently, the P1NP/CTX-I ratio was significantly decreased in the vegetarians. The children following a vegetarian diet showed impaired bone metabolism with reduced bone formation and increased bone resorption. Higher levels of decorin, a myokine involved in collagen fibrillogenesis and essential for tissue structure and function, may suggest a potential compensatory mechanism contributing to maintaining bone homeostasis in vegetarians. The observed significant positive correlations between myostatin and bone metabolism markers, including P1NP and soluble receptor activator of nuclear factor kappa-B ligand (sRANKL), suggest an interplay between muscle and bone metabolism, potentially through the RANK/RANKL/OPG signaling pathway.

3D-printed bone regeneration scaffolds modulate bone metabolic homeostasis through vascularization for osteoporotic bone defects.

The treatment of osteoporotic bone defects poses a challenge due to the degradation of the skeletal vascular system and the disruption of local bone metabolism within the osteoporotic microenvironment. However, it is feasible to modulate the disrupted local bone metabolism imbalance through enhanced vascularization, a theory termed "vascularization-bone metabolic balance". This study developed a 3D-printed polycaprolactone (PCL) scaffold modified with EPLQLKM and SVVYGLR peptides (PCL-SE). The EPLQLKM peptide attracts bone marrow-derived mesenchymal stem cells (BMSCs), while the SVVYGLR peptide enhances endothelial progenitor cells (EPCs) vascular differentiation, thus regulating bone metabolism and fostering bone regeneration through the paracrine effects of EPCs. Further mechanistic research demonstrated that PCL-SE promoted the vascularization of EPCs, activating the Notch signaling pathway in BMSCs, leading to the upregulation of osteogenesis-related genes and the downregulation of osteoclast-related genes, thereby restoring bone metabolic balance. Furthermore, PCL-SE facilitated the differentiation of EPCs into "H"-type vessels and the recruitment of BMSCs to synergistically enhance osteogenesis, resulting in the regeneration of normal microvessels and bone tissues in cases of femoral condylar bone defects in osteoporotic SD rats. This study suggests that PCL-SE supports in-situ vascularization, remodels bone metabolic translational balance, and offers a promising therapeutic regimen for osteoporotic bone defects.